The human photoreceptor membrane guanylyl cyclase, RetGC, is present in outer segments and is regulated by calcium and a soluble activator

doi:10.1016/0896-6273(94)90449-9

Neuron

Volume 12, Issue 6, June 1994, Pages 1345-1352

https://doi.org/10.1016/0896-6273(94)90449-9 Get rights and content

Abstract

A human photoreceptor membrane guanylyl cyclase, RetGC, was recently cloned and expressed, but its localization and manner of regulation were not defined. We report here that RetGC is detected primarily in outer segments of human photoreceptor cells. Recombinant RetGC can be stimulated by a soluble retinal-specific factor. Ca²⁺ interferes with stimulation of RetGC by this factor with a cooperativity coefficient of 1.7 and EC₅₀ near 200 nM. The Ca²⁺ sensitivities of recombinant RetGC and of guanylyl cyclase activity from rod outer segment membranes are very similar. Our findings indicate that RetGC is a photoreceptor-specific guanylyl cyclase which is stimulated by a retinal-specific activator and inhibited by physiologically relevant concentrations of free Ca²⁺. The Ca²⁺ sensitivity of RetGC may be responsible for some of the previously reported effects of Ca²⁺ on light adaptation and recovery of the dark state.

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Citation Excerpt :
Cone photoreceptor-mediated vision improved within a month after an antisense oligonucleotide intravitreal injection (Cideciyan et al., 2019). A human GUCY2D gene codes for retinal guanylyl cyclase isozyme-1, RetGC1 (Dizhoor et al., 1994; Lowe et al., 1995). A spectrum of retinal disease is associated with mutations in the GUCY2D gene, including autosomal dominantly inherited cone-rod and cone degenerations and autosomal recessive LCA.
A first-in-human clinical trial of gene therapy in Leber congenital amaurosis due to mutations in the GUCY2D gene is underway, and early results are summarized. A recombinant adeno-associated virus serotype 5 (rAAV5) vector carrying the human GUCY2D gene was delivered by subretinal injection to one eye in three adult patients with severe visual loss, nystagmus, but preserved retinal structure. Safety and efficacy parameters were monitored for 9 months post-operatively. No systemic toxicity was detected; there were no serious adverse events, and ocular adverse events resolved. P1 and P2 showed statistically significant rod photoreceptor vision improvement by full-field stimulus testing in the treated eye. P1 also showed improvement in pupillary responses. Visual acuity remained stable from baseline in P1 and P2. P3, however, showed a gain of 0.3 logMAR in the treated eye, indicating greater cone-photoreceptor function. The results show safety and both rod- and cone-mediated efficacy of this therapy.

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Neuron

ArticleThe human photoreceptor membrane guanylyl cyclase, RetGC, is present in outer segments and is regulated by calcium and a soluble activator

Abstract

J. Biol. Chem.

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J. Biol. Chem.

J. Biol. Chem.

FEBS Lett.

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Vision Res.

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Methods Enzymol.

Differential activation by atrial and brain natriuretic peptides of two receptor guanylate cyclases

Nature

Molecular cloning of a new type of cell surface receptor: a membrane form of guanylate cyclase is an atrial natriuretic peptide receptor

Nature

Article
The human photoreceptor membrane guanylyl cyclase, RetGC, is present in outer segments and is regulated by calcium and a soluble activator